Abstract
Thyroid hormone (TH) is crucial for development and metabolism of many tissues. The physiological relevance and therapeutic potential of TH analogs have gained attention in the field for many years. In particular, the relevance and use of 3,3′,5-triiodothyroacetic acid (Triac, TA3) has been explored over the last decades. Although TA3 closely resembles the bioactive hormone T3, differences in transmembrane transport and receptor isoform-specific transcriptional activation potency exist. For these reasons, the application of TA3 as a treatment for resistance to TH (RTH) syndromes, especially MCT8 deficiency, is topic of ongoing research. This review is a summary of all currently available literature about the formation, metabolism, action and therapeutic applications of TA3.
Introduction
Thyroid hormone (TH) is crucial for the development and metabolism of many tissues. Thyroid stimulating hormone (TSH) controls the production and secretion of TH by the thyroid gland, which predominantly produces the pro-hormone thyroxine (T4) and to a lesser extent the bioactive hormone 3,3′,5-triiodothyronine (T3). T3 mainly exerts its effects through binding to its nuclear receptors (TRs) at T3 response elements (TREs), resulting in the transcriptional regulation of TH target genes (genomic effects). The TRα1, TRβ1 and TRβ2 isoforms are T3-binding TRs isoforms (Lazar 1993, Ortiga-Carvalho et al. 2004). In addition, several non-genomic effects have been ascribed to TH (Davis et al. 2011, Lin et al. 2012). To exert its biological function, TH has to cross the cell membrane, which requires membrane transporter proteins (Hennemann et al. 2001 and reviewed in Visser 2007 and Bernal et al. 2015). Monocarboxylate transporter 8 (MCT8) is the most specific TH transporter and the only TH transporter associated with human disease (Dumitrescu et al. 2004, Friesema et al. 2004). The deiodinases (D1–3) importantly regulate the bio-availability of T3 in targets cells, while TH is also metabolized by glucuronidation and sulfation, which enhance biliary excretion (Engler & Burger 1984, Burger 1986, Visser 1996). Other modifications of iodothyronines include decarboxylation of the alanine side chain, resulting in iodothyronamines (Scanlan et al. 2004, Hoefig et al. 2015), and subsequent oxidative deamination resulting in the formation of iodothyroacetic acid derivatives (Wood et al. 2009). Recently, potential biological actions have been ascribed to 3-iodothyronamine (3-T1AM) and thyronamine (T0AM) (reviewed in Hoefig et al. 2016). The biological actions of 3,3′,5-triiodothyroacetic acid (Triac; TA3) and 3,3′,5,5′-tetraiodothyroacetic acid (Tetrac, TA4) have been more extensively described. The biological actions of TA3 closely resemble those of T3, although important differences in the cellular transport mechanism and TR-isoform-specific potency exist. For these reasons, TA3 holds therapeutic potential in the treatment of patients with specific defects in TH signaling, such as patients harboring mutations in TRβ (resistance to thyroid hormone (RTH)-β). Likewise, the therapeutic use of TA3 in patients lacking the MCT8 transporter (MCT8 deficiency or the Allan-Herndon-Dudley syndrome, AHDS) is subject of ongoing research.
In this review we summarize the literature from the 1950s until now regarding the biosynthesis, metabolism, action and putative therapeutic applications of TA3.
Kinetic properties of TA3 in humans
TA3 is a naturally occurring TH metabolite, with reported serum levels between 2.6 and 15.2 ng/dL (42–244 pmol/L) in healthy human subjects (Nakamura et al. 1978, Burger et al. 1979, Gavin et al. 1980), whereas others reported TA3 levels below the assay detection limit of ~4 ng/dL (64 pmol/L) (Menegay et al. 1989). The free fraction of TA3 in plasma is relatively low compared to T3, due its high affinity for plasma binding proteins, exceeding that of T3 by 16-fold in rats (Ingbar 1960, Gosling et al. 1976). In humans, TA3 particularly binds to transthyretin (TTR), whereas its binding to thyroxine binding globulin is negligible (Robbins & Rall 1955, Christensen 1960, Ingbar 1960). Nevertheless, the plasma clearance rate of TA3 considerably exceeds the clearance rate of T3 in humans (compiled data shown in Table 1). The clearance rate of TA3 in rats is more similar to that of T3 (Table 1; Gosling et al. 1976, Liang et al. 1997). In humans, the estimated plasma half-life of TA3 is ~6 h and, thus, is markedly shorter than the half-life of T3 (~24 h) (Table 1). Peak levels occur within 40 min after oral administration and higher peak levels are achieved upon intravenous administration (Menegay et al. 1989). The intestinal absorption efficiency amounts to 50–67% and the daily TA3 production rate (PR) to 3.2–7.8 µg/day (Burger et al. 1979, Gavin et al. 1980, Siegrist-Kaiser et al. 1994). Gavin and coworkers (Gavin et al. 1980) found a slightly higher PR in athyroid subjects on 80 µg/day LT3 substitution (10.1 ± 0.4 µg/day). A caveat in assessing circulating TA3 concentrations is the interference of T3 in the TA3 radioimmunoassay (RIA) due to high antibody cross-reactivity (up to 50%). When preceded by proper serum extraction and column chromatography methods, this can be reduced to 1–6% (Burger et al. 1979, Gavin et al. 1980, Menegay et al. 1989). Since serum T3 levels exceed those of TA3 by about 50-fold, this leads to considerable overestimation of endogenous TA3 levels.
Kinetic properties of T3 and TA3 in humans and rats.
| Species/substrate | Serum level (pmol/L) | Peak levels (min) | t1/2 (h) | MCR (L/day) | Major binding protein | PR (µg/day) | References |
|---|---|---|---|---|---|---|---|
| Human | |||||||
| T3 | 1736 ± 168 | 120–180 | 23 | 22.4–36.5 | TBG | 40.6 ± 2.1 | Robbins & Rall (1955), Christensen (1960), Green & Ingbar (1961), Oppenheimer (1974), Burger & Vallotton (1975), Chopra (1976), Gavin et al. (1977, 1980), Nakamura et al. (1978), Burger et al. (1979), Pittman et al. (1980), Engler et al. (1984), Menegay et al. (1989), Lopresti & Dlott (1992) |
| TA3 | 42–244 | 40 | 6.5 ± 0.5 | 222–298 | TTR | 5.2 ± 1.5 | |
| Rat | |||||||
| T3 | 768 | – | ~2 | 4.2–7.3 | 2.3–2.5 | Wilkinson et al. (1959), Gosling et al. (1976), Cavalieri et al. (1984), Nguyen et al. (1993), Liang et al. (1997) | |
| TA3 | 402 | – | ~1 | 3.5–9.4 | |||
Overview of kinetic properties of T3 and TA3 in humans and rats. Data are compiled from indicated references. Peak levels have been determined after oral administration.
MCR, metabolic clearance rate; PR, production rate; t 1/2, plasma half life time; TBG, thyroxine binding globulin, TTR, transthyretin.
Together, TA3 is a naturally occurring TH metabolite, present in humans at ~50-fold lower concentrations than T3 and is rapidly cleared from the circulation despite its high affinity for plasma binding proteins.
Biosynthesis of TA3
The first evidence for in vivo TA3 formation was provided by studies in thyroidectomized rats demonstrating the presence of 131I-TA3 in kidney homogenates after injection of 131I-T3 (Jouan et al. 1956). These findings were confirmed by incubation of rat kidney mitochondrial extracts (Albright et al. 1956), and rat kidney (Tomita et al. 1957) or brain (Tata et al. 1957) homogenates with 131I-T4 and 131I-T3. More recent studies confirmed the in vivo formation of TA3 upon T3 injection in rats (Medina-Gomez et al. 2008). In vivo formation of TA3 and TA4 was demonstrated in humans after administration of 125I-LT4 (Braverman et al. 1970), whereas others detected TA3 after the administration of 125I-TA4 (Burger et al. 1979, Burger 1986) Based on these findings it was assumed that T3 and/or TA4 are intermediates in the conversion of T4 to TA3.
The mechanism by which iodothyronines are converted to iodothyroacetic acid metabolites has not been fully elucidated. A common hypothesis involves the decarboxylation and successive oxidative deamination of the alanine side chain of iodothyronines. Recently, purified human intestinal ornithine decarboxylase (ODC) was indeed demonstrated to facilitate the decarboxylation of 3,5-T2 to 3,5-diiodothyronamine (T2AM) and T4 to 3,3′,5,5′-tetraiodothyronamine (T4AM) (Hoefig et al. 2015). The involvement of aromatic l-amino acid decarboxylase (AADC, or l-DOPA decarboxylase), long regarded as the most likely candidate, has been disproven (Hoefig et al. 2012). It remains to be studied if other decarboxylases also possess this capacity. Although, recent studies have demonstrated the presence of decarboxylated (iodo)thyronine metabolites 3-T1AM and T0AM in vivo (Scanlan et al. 2004), other iodothyronamines have not been detected in human serum thus far.
The oxidative deamination of T1AM and T3AM to their thyroacetic acid counterparts has been demonstrated in HepG2 cells and human thyroid tissue and was reduced by iproniazide, an inhibitor of monoamine oxidase (MAO) and semicarbazide-sensitive amine oxidase (Wood et al. 2009). It was suggested that at least one of these enzymes converts 3-T1AM and T3AM to their aldehyde intermediates, which may be substrates for the abundantly expressed aldehyde dehydrogenase (ALDH), resulting in the formation of 3-iodothyroacetic acid (3-TA1) and TA3, respectively (Wood et al. 2009). Of interest, TA3 modulates the activity of ALDH (McCarthy et al. 1968, Mårdh et al. 1987, Zhou & Weiner 1997). Conversion of T4AM to TA4 has not been demonstrated thus far. Although iodothyronamines are efficiently deiodinated, neither D1 nor D2 catalyzes the conversion of T4AM to T3AM (Piehl et al. 2008). This indicates that conversion of T4AM to T3AM is not an intermediate step in the conversion of T4 to TA3 (Fig. 1). Together, these studies support the hypothesis that at least some iodothyronines can be converted to their acetic acid metabolites via a thyronamine intermediate. An alternative route for the metabolism of the alanine side chain of iodothyronines involves its conversion by aminotransferase(s) to pyruvic acid, followed by decarboxylation to acetaldehyde and oxidation to acetic acid (e.g. Wilkinson 1957). However, the enzymes catalyzing these reactions remain to be identified.
Schematic overview of cellular formation, metabolism and action of TA3. Dashed lines represent processes for which the involved enzymes/transporters have not been identified but their existence may be assumed based on theoretical grounds or experimental data. D, deiodinase; MAO, monamine oxidase; SSAO, semicarbazide-sensitive amine oxidase; ODC, ornithine decarboxylase; TK3, 3,3′,5-triiodothyropyruvic acid.
Citation: Journal of Endocrinology 234, 2; 10.1530/JOE-17-0113
Metabolism of TA3
TA3 has been shown to be metabolized via similar pathways as T3, i.e. stepwise deiodination, and conjugation with glucuronic acid and sulfate.
Deiodination
Early studies found that TA3 inhibits inner ring deiodination (IRD) of T3 in rat brain microsomes (Kaplan et al. 1983) and monkey hepatocellular carcinoma cells (Sorimachi & Yasumura 1981). Later studies demonstrated that TA3 is efficiently deiodinated to 3,3′-diiodothyroacetic acid (3,3′-TA2) by D1 and D3 (Rutgers et al. 1989a, Horn et al. 2013). TA3 is even a better substrate for D1 than T3, illustrated by a 16-fold higher Vmax/Km ratio (Rutgers et al. 1989a). Similar to T3, TA3 induced the expression and activity of D1 in rat liver and kidney (Medina-Gomez et al. 2008). Moreover, outer ring deiodination by Dio1 and Dio2 mediates the conversion of TA4 to TA3 (Burger et al. 1975, Köhrle et al. 1986, Horn et al. 2013).
In humans, up to 60% of the administrated 131I-TA3 dose appears in urine as inorganic 131I within 24 h (Green & Ingbar 1961), suggesting that deiodination of (conjugated) TA3 comprises an important metabolic pathway in vivo. In contrast, Flock and coworkers (Flock et al. 1962) found that only 20% of 131I-TA3 administered to dogs appeared as inorganic 131I in urine within 24 h, while 3,3′-TA2 sulfate was also detected in serum. A similar fraction of 131I-TA3 was excreted in urine as inorganic 131I in rats (Wilkinson et al. 1959, Juge-Aubry et al. 1995).
Deiodination of TA3 ultimately results in the formation of thyroacetic acid (TA0), which is excreted in urine in humans (Chopra et al. 1988). Given that the estimated PRs of TA4 and TA3 together amount to ~10 µg/day (Pittman et al. 1980, Siegrist-Kaiser & Burger 1994), the urinary TA0 levels (up to ~15 µg/L) cannot be derived from deiodination of endogenous TA4 and TA3 alone. Based on the studies of Hoefig and coworkers (Hoefig et al. 2015) and Wood and coworkers (Wood et al. 2009), the metabolism of (iodo)thyronines such as 3,5-T2, 3-T1 and T0 via thyronamine intermediates to their thyroacetic acid derivatives also contributes to urinary TA0 excretion.
Conjugation
In addition to deiodination, conjugation of TA3 to its glucuronide (TA3G) and sulfate (TA3S) constitutes an important part of TA3 metabolism. Incubation of rat hepatocytes with 131I-TA3 results in almost complete metabolism of TA3 within 3 h, mainly to TA3G (50%), 131I− (40%) and TA3S (<10%) (Rutgers et al. 1989b). The formation of TA3G and TA3S increases to 60% and 16%, respectively, by blocking Dio1 with propylthiouracil (PTU), and TA3G levels even further increase to 80% by simultaneous inhibition of sulfation, without affecting total TA3 metabolism (Rutgers et al. 1989b).
Similar to sulfated iodothyronines, TA3S is rapidly degraded through IRD (Rutgers et al. 1989a). The aryl sulfotransferase Sult1a1 (or phenol sulfotransferase 1 (PST1)) mediates the sulfation of TA3 at the 4′-hydroxyl group in rats (Sekura et al. 1981) and the ubiquitously expressed (human) SULT1A1 is the most likely candidate in humans (Visser 1994). In rats, stable ether glucuronides are formed at the phenolic hydroxyl group of TA3, whereas mainly labile ester glucuronides at the carboxyl group are formed in humans (Burger 1986, Moreno et al. 1994).
Although deiodination of TA3S appears to be the principal metabolic route of TA3 in humans, TA3G is the major TA3 metabolite excreted in bile (Roche et al. 1956, Green & Ingbar 1961). Up to 50% of 131I-TA3 administered to rats is excreted within 4 h as TA3G in bile (Rutgers et al. 1989b), suggesting that glucuronidation is also the main route of TA3 metabolism in rats. Interestingly, serum TA3S and biliary TA3G and TA3S excretion are increased by blocking deiodination with PTU, without affecting the TA3 clearance rate. Flock and coworkers (Flock et al. 1965) obtained similar results using another D1 inhibitor, butyl 4-hydroxy-3,5-diiodobenzoate (BHDB). Bilirubin glucuronosyltransferase-deficient Gunn rats show a reduction in biliary excretion of TA3G, accompanied by a compensatory increase of non-specified metabolites in urine (Flock et al. 1965). Moreover, newborn sheep reveal a rapid decrease of TA3S plasma levels which coincides with the maturation of glucuronosyltransferase (and deiodinase) expression (Wang et al. 1986, Wu et al. 2008). Lastly, hepatectomized dogs show complete abolishment of TA3G formation and a concomitant increase in sulfate conjugates in plasma and urine, most predominantly 3′-TA1S and 3,3′-TA2S (Flock et al. 1962).
Together, these studies suggest that deiodination and conjugation are responsible for a stable TA3 clearance, even in case one of these pathways is not properly functioning. Importantly, since the relative contribution of these pathways differs across species, metabolic and kinetic studies in animal models should be extrapolated to different models with caution.
Cellular transport of TA3
As for TH, the cellular entry of TA3 is supposed to be transporter-mediated. Studies using rat anterior pituitary cells and cardiomyocytes have shown a similar time course of 125I-TA3 and 125I-T3 uptake (Everts et al. 1994, Verhoeven et al. 2002). Based on free hormone levels, the transport rate of TA3 even exceeds that of T3 (Everts et al. 1994, Verhoeven et al. 2002). Moreover, TA3 competes with TH uptake in rat anterior pituitary cells and isolated hepatocytes, but not in rat cardiomyocytes (Blondeau et al. 1988, Everts et al. 1994, Neves et al. 2002, Verhoeven et al. 2002). These findings suggest that tissue-specific transporters facilitate the cellular entry of TA3, some of which may work in an ATP and sodium independent manner (Everts et al. 1994).
TA3 transporters have not been identified yet. MCT8, MCT10 and Organic Anion Transporting Polypeptide (OATP)1C1 do not appear relevant for transport of TA3 (Horn et al. 2013, Groeneweg et al. 2014, Kersseboom et al. 2014). Studies in rodents suggest that the TA3 transporter(s) are widely expressed, given the increase in TA3 levels in many tissues after injection of TA3 (Medina-Gomez et al. 2008, Kersseboom et al. 2014). However, the transporter(s) involved remain to be identified.
Molecular basis of TA3 action
TA3 binds efficiently to nuclear TRs (Oppenheimer et al. 1973, Smith et al. 1980, Evans et al. 1983, Bres et al. 1986, Luo et al. 1986), i.e. with a similar affinity as T3 to TRα1 and a 3- to 6-fold higher affinity than T3 to TRβ1 and TRβ2 (Schueler et al. 1990, Takeda et al. 1995, Messier & Langlois 2000, Martínez et al. 2009), which may indicate relative TRβ-selective binding and action of TA3. This is supported by a 2- to 3-fold lower EC50 value for TRβ1 compared to TRα1 mediated transcriptional activation by TA3 (Martínez et al. 2009). The preferential binding of TA3 to TRβ is supported by X-ray crystallography (Martínez et al. 2009). Although TA3 shows a better fit in the TRα1 ligand binding cavity, its binding to TRβ is more energetically favorable. This is mainly caused by a single amino acid difference between TRα1 (Ser277) and TRβ1 (Asn331) at the ligand binding domain (LBD), leading to a relative displacement of the β-hairpin of the TRβ LBD which potentiates direct substrate contacts (Wagner et al. 2001, Martínez et al. 2009). Of clinical importance is the relatively high affinity of TA3 for several TRβ mutants identified in patients with RTH-β which display reduced T3 binding (Takeda et al. 1995, Messier et al. 2001).
Importantly, despite its higher affinity for TRβ than T3, controversy exists to what extent this leads to higher transcriptional activation levels. Messier and Langlois (2000) did not observe differences in TRβ-mediated transcriptional activation potency between T3 and TA3 in case of the direct repeat (DR4), the most prevalent TRE configuration in humans (Yen 2001), whereas TA3 was 1.5- to 2-fold more potent than T3 in case of palindrome and inverted palindrome TREs. In contrast, Martínez and coworkers (Martínez et al. 2009) found that TA3 was also 6-fold more potent than T3 in activating TRβ-mediated transcription in case of DR4.
Although not studied in detail, differences in the potency of TA3 and T3 to dissociate or recruit co-factors may exist. It was found that TA3 has a lower efficacy than T3 in recruiting the steroid receptor co-activator (SRC-1) to TRα1 (Koury et al. 2009). Of note, most of these studies have been carried out in the absence of retinoid X receptor (RXR), which has been shown to exert a central role in modulating the sensitivity of TH-responsive genes to different TR ligands (Bogazzi et al. 1997).
The non-genomic effects of TA3 have been scarcely studied (Lin et al. 1998, D’Arezzo et al. 2004). TA3 was found to exert a stimulatory effect on the plasma membrane integrin αvβ3 receptor, although less potently compared to T3 (D’Arezzo et al. 2004). Taken together, TA3 has somewhat higher affinity and transcriptional activation potency for TRβ than TRα and, thus, may exert stronger thyromimetic effects in TRβ-expressing tissues. However, it should be realized that intracellular TA3 levels are governed by tissue-specific transporters, deiodinases and conjugating enzymes which also impact the tissue-specific biological actions of TA3.
Regulation and role of TA3
TA3 is an important bioactive hormone in marine invertebrates. Interestingly, the TR of Branchiostoma floridae (amphioxus) is selectively activated by TA3 and not by T3 (Paris et al. 2008, Wang et al. 2009). Nevertheless, administration of T3 to the developing amphioxus stimulates its metamorphosis (Paris et al. 2010), suggesting that T3 is a precursor of the bioactive hormone TA3. Indeed, TA3 is present in amphioxus and its administration promotes metamorphosis to a similar extent as administration of T3 (Paris et al. 2008, 2010). In addition, the non-selenodeiodinase bfDy from B. floridae specifically catalyzes the IRD of TA4 and TA3 but not of T4 and T3 (Klootwijk et al. 2011). Also in other species, TR activation by TA3 may differ from the human situation (Oka et al. 2013).
Although TA3 is a naturally occurring bioactive TH metabolite in humans, its exact biological role is unknown. In addition, little is known about factors that affect its serum and tissue concentrations. Several studies found up to 3-fold increased serum TA4 and TA3 levels during fasting and non-thyroidal illness (Burger et al. 1976, Pittman et al. 1980, Dlott et al. 1992, LoPresti & Dlott 1992). It was suggested that the reduction in D1 and increase in D3 activity during these ‘low T3 states’, favor the formation of rT3 and other TH metabolites such as TA3 (Carlin & Carlin 1993, Farwell 2013). Indeed, urinary excretion of TA3(S) is increased during fasting and iopanoic acid (IOP) treatment (LoPresti et al. 1993, Kaiser-Siegrist & Burger 1994). The molecular basis for these changes is largely unclear, although the role of ODC appears to be limited, since its activity is reduced during starvation (D’Agostino et al. 1987). It has been postulated that the increased TA3 levels are responsible for the suppression of TSH observed under these conditions despite low serum TH levels. In addition, TA3 potently suppresses leptin secretion by rat brown and white adipocytes, and since leptin stimulates TSH secretion this may induce a further decline in TSH levels (Medina-Gomez et al. 2004).
Effects of TA3 on the hypothalamus–pituitary–thyroid (HPT) axis
The first recognized effect of TA3 was the reduction of goiter in hypothyroid rats (Pitt-Rivers 1953). In line, TA3 effectively restores most clinical and biochemical abnormalities in myxedematous patients (Pitt-Rivers 1955, 1956, Trotter 1955, 1956). Later studies showed that TA3 potently reduces TSH secretion and TRH-receptor expression in mouse thyrotropic pituitary tumor cells (Gershengorn et al. 1979) and TRH-induced TSH release from rat pituitary fragments or cells (Szabolcs et al. 1991, Everts et al. 1994).
In euthyroid and hypothyroid rats, a dose-dependent reduction of serum TSH levels is observed within 6 h after TA3 administration, beginning at a dose as low as 10 µg/kg (Table 2). From these and other studies it was estimated that 62 µg (100 nmol)/kg/day TA3 has an equal TSH-suppressive effect as 16 µg (20 nmol)/kg/day LT4. Interestingly, Mirell and coworkers (Mirell et al. 1989) found that TSH mRNA expression levels are unchanged 6 h after TA3 administration, suggesting that the initial decline in serum TSH is not caused by alterations at transcriptional level, but rather points to direct inhibition of TSH secretion by TA3. In contrast, prolonged (>12 days) TA3 administration to rats persistently suppressed pituitary TSH mRNA levels (Juge-Aubry et al. 1995, Liang et al. 1997), resulting in a dose-dependent decrease in serum T3 and T4 levels (Medina-Gomez et al. 2008). Similar effects on TSH levels were found in mice treated with TA4, whereas no effects were observed on hypothalamic TRH mRNA expression (Horn et al. 2013).
Tissue effects of TA3 determined in animal studies.
| Parameter | Effect/outcome | Species, thyroid state | Dose; duration; mode of administration | References |
|---|---|---|---|---|
| HPT-axis* | ||||
| TSH (serum) basal or stim. | ↓ | Rat, eu/hypo | 10 µg/kg/day; 12 day; i.v. | Mirell et al. (1989), Juge-Aubry et al. (1995), Liang et al. (1997), Alvarez et al. (2004), Medina-Gomez et al. (2008) |
| T4 (serum) | ↓ | Rat, eu | 8 µg/kg/day; 12 day; i.v. | Medina-Gomez et al. (2008) |
| T3 (serum) | ↓ | Rat, eu | 40 µg/kg/day; 12 day; i.v. | Medina-Gomez et al. (2008) |
| Thyroid weight | ↓ | Rats, hypo | ~5 µg/kg/day; 9 day; s.c. | Pitt-Rivers (1953) |
| Heart | ||||
| Heart weight/body weight | ↑ | Rat (adult), hypo | 300 µg/kg/day; 15 day | Olsen et al. (1977), Liang et al. (1997) |
| ↑ | Rat (newborn) | 300 µg/kg/day; 1 year | Symons et al. (1975) | |
| ↑ | Rat (in utero) | 300 µg/kg/day; 15 day to pregnant dams | Olsen et al. (1977), Hawkey et al. (1981) | |
| Cardiomyopathy | + | Rat (in utero) | >300 µg/kg/day; 15 day to pregnant dams | Olsen et al. (1977), Hawkey et al. (1981) |
| Rat (newborn) | 300 µg/kg/day; 1 year | Symons et al. (1975) | ||
| Cardiac size | ↑ | Rat (adults) | 180 µg/kg/day; 1 year | Symons et al. (1975), Olsen et al. (1977) |
| Bone | ||||
| Bone formation markers (serum) | = | Rat, eu/hypo | 250 µg/kg/day; 40 day; i.p. | Alvarez et al. (2004) |
| Bone resorption markers (serum) | = | Rat, eu | 250 µg/kg/day; 40 day; i.p. | Alvarez et al. (2004) |
| ↑ | Rat, hypo | 250 µg/kg/day; 40 day; i.p. | Alvarez et al. (2004) | |
| BMD | = | Rat, eu/hypo | 250 µg/kg/day; 40 day; i.p. | Alvarez et al. (2004) |
| Brain | ||||
| Myelination | ↑ | Mice, hypo | 200 µg/kg/day; 12 day; oral | Kersseboom et al. (2014), Zada et al. (2016) |
| Zebrafish, hypo | ||||
| Purkinje cell development | ↑ | Mice, hypo | 200 µg/kg/day; 12 day; oral | Kersseboom et al. (2014), Delbaere et al. (2017) |
| Chicken, hypo | ||||
| Liver | ||||
| Cholesterol | = | Rats, eu | 200 µg/kg/day; 4 week; oral | Autissier et al. (1980) |
| Biliary cholesterol | = | Rat, eu | 1000 µg/kg/day; 9 day; i.v. | Van Zyl (1957) |
| Biliary cholic acid | ↓ | Rat, eu | 1000 µg/kg/day; 9 day; i.v. | Van Zyl (1957) |
| Metabolism | ||||
| Oxygen consumption | Acute ↑ | Rats, hypo | 1000 µg/kg; single; s.c. | Pitt-Rivers (1953), Wilkinson (1959) |
| Gradual ↑ | 600 µg/kg; 4 day; s.c. | Hill et al. (1960) | ||
| Body weight | ↓ | Rats, hypo | 60 µg/kg/day; 9 day; s.c. | Pitt-Rivers (1953) |
Explanation of symbols: =, no effect; ↑, stimulatory effect; ↓, inhibitory effect; +, present. In case of =, the highest dose reported to have no effects is listed in the 4th column. In case of ↑ or ↓ the lowest dose at which the effect has been reported is listed in the 4th column.
Only the studies that corrected for cross-reactivity of TA3 in the T3 assay are listed.
i.p., intraperitoneal; i.v., intravenous; s.c., subcutaneous; stim., TRH-stimulated.
A dose-dependent reduction of TSH levels was observed within 6–9 h after oral administration of TA3 to euthyroid human subjects, with a lowest dose of 350 µg (~5 µg/kg) (Burger et al. 1979, Medeiros-Neto et al. 1980, Menegay et al. 1989). Similar effects were observed in hypothyroid subjects and subjects with apparent TH insensitivity (Beck-Peccoz et al. 1983, Salemla et al. 1988, and Table 3). Consequently, serum T4, rT3 and T3 levels decrease (Burger et al. 1979, Medeiros-Neto et al. 1980, Beck-Peccoz et al. 1983, 1988, Bracco et al. 1993). Sustained TSH suppression was best achieved upon division of the daily TA3 dose compared with a single morning administration, although both regimes resulted in a similar reduction of serum T4 levels (Medeiros-Neto et al. 1980, Bracco et al. 1993).
Tissue effects of TA3 determined in humans.
Overview of the effects of TA3 in humans. Details on the dosing, follow-up time and group size of these individual studies can be found in Table 4. Explanation of symbols: =, no effect; ↑, stimulatory effect of TA3; ↓, inhibitory effect of TA3. In case of =, the highest dose reported to have no effects is listed in the 4th column. In case of ↑ or ↓ the lowest dose at which the effect has been reported is listed in the 4th column.
Only the studies that corrected for cross-reactivity of TA3 in the T3 assay are listed.
BMR, basal metabolic rate; CHD, coronary heart disease; i.v., intravenous; RMR, resting metabolic rate; SEE, sleeping energy expenditure.
Taken together, TA3 inhibits TSH production and secretion by acting at the level of the pituitary, thereby regulating thyroid activity.
Effects of TA3 on other tissues
In addition to its potent effect on the HPT axis, TA3 also exerts thyromimetic effects on peripheral tissues (Tables 2 and 3). In evaluating these effects, it should be taken into account that TA3 reduces endogenous TH production when administrated to euthyroid subjects, which also contributes to the changes in tissue TH status. Therefore, the direct effects of TA3 can best be studied in athyroid subjects. An overview of clinical studies with TA3 in humans is provided in Table 4. Table 5 provides an overview of the thyromimetic potency of TA3 in different tissues relative to T4. TA3 and LT4 dose are expressed in μg/kg (if available) or else as total daily dose. Bone formation markers include alkaline phosphatase and osteocalcin (in case of discrepant responses of these parameters within the same study, the response of osteocalcin prevails since this is a more specific marker for bone formation). Bone resorption markers include hydroxyproline or d-pyridinoline (in case of discrepant responses the parameter with the strongest response prevails). In case TA3 and LT4 monotherapy are compared, tissue sensitivity is expressed as TA3 dose/LT4 dose ratio required to obtain a similar effect size on the given parameters. In case of comparison between LT4 + TA3 vs LT4 mono-therapy, tissue sensitivity is expressed relative to the TA3 dose/Δ LT4 dose ratio (e.g. <(ratio) means a stronger response of the parameter to low dose LT4 + TA3 compared to the high dose LT4 mono-therapy at an equal TSH-suppressive dose). Only studies in which details of >2 organ systems have been provided are included in Table 5.
Overview of clinical studies in humans.
| Effects of TA3 | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Reference | Thyroid state | Daily dose of TA3 (µg/day) | Duration | TSH | Chol | Bone TO | BW | BMR | HR | Myx | Side effects | Conclusion(s) |
| Myxedema or hypothyroidism | ||||||||||||
| Lerman & Pitt-Rivers (1955) | Hypo | 1000–4000, i.v. | 16–17 day | ↓ | ↓ | = | ↓ | Normalization of myxedematous features | ||||
| Lerman & Pitt-Rivers (1956) | Hypo | 100–4000, i.v. | 12–16 day | ↓ | ↓ | ↑ | ↓ | Normalization of myxedematous features; higher doses were required to restore BMR | ||||
| Trotter (1955) | Hypo | 2000–6000, oral | 10 day | ↓ | ↓ | ↓ | ↓ | Normalization of myxedematous features | ||||
| Trotter (1956) | Hypo, eu | 1000–6000, oral | 2–28 week | ↓ | ↓ | Normalization of myxedematous features | ||||||
| Rall (1956) | Hypo | 5000–15,000, single dose i.v. | 36 day follow-up | ↓ | ↑ | Normalization of myxedematous features | ||||||
| De Graeff et al. (1957) | Hypo | 1000, i.v. | 12 day | ↓ | ↓ | = | ↓ | Normalization of myxedematous features | ||||
| Ibbertson et al. (1959) | Hypo | 10,000–18,000, single dose oral500–6000, oral | 3–10 months | ↓ | ↓ | ↑ | ↓ | a | Normalization of myxedematous features; higher doses were required to restore BMR | |||
| Lerman (1961) | Hypo | 500–4000, i.v. | 2–3 months | ↓ | = | Normalization of myxedematous features; higher doses were required to restore BMR | ||||||
| Hill et al. (1960) | Hypo | 1000–6000, oral | 14–52 day | ↓ | ↑ | Normalization of myxedematous features at >4000 µg/day | ||||||
| Zondek et al. (1956) | Hypo | 8000–10,000, 2 day oral | 15 day follow-up | (↓) | ↑ | ↓ | Temporary normalization of myxedematous features | |||||
| Lipid-reduction in coronary heart disease | ||||||||||||
| Oliver & Boyd (1957) | Eu | 500–5000, oral | 12–14 week | (↓) | = | = | b | Not useful for lipid lowering in patients with pre-existent heart disease | ||||
| Boyd & Oliver (1960) | Hypo, eu | 500–5000, oral | >12 week | (↓) | c | Not useful for lipid lowering in patients with pre-existent heart disease | ||||||
| Treatment of euthyroid goiter | ||||||||||||
| Brenta et al. (2003) | Eu | 1400, oral | 11 months | ↓ | ↓ | ↑ | = | Effective reduction of goiter size, with fewer side-effects (e.g. palpitations) | ||||
| Pujol et al. (2000) | Eu | 1400, oral | 12–21 month | = | d | No thyromimetic (side) effects on the heart in long-term treated patients | ||||||
| Thyroid carcinoma (substitution after thyroid ablation) | ||||||||||||
| Mueller-Gaertner & Schneider (1988) | Hypo | 500 (+LT4), oral | 3 week | ↓ | e | Addition of a low dose TA3 to LT4 mono-therapy further reduced basal and stimulated TSH levels | ||||||
| Sherman & Ladenson (1992) | Hypo | 1400 (+LT4), oral | 6–8 week | ↓ | ↓ | ↑ | = | = | = | Compared to LT4 alone, a 40–50% lower LT4 dose was required if combined with TA3 to obtain equivalent or even better TSH suppression, without affecting TH action in peripheral tissues | ||
| Sherman et al. (1997) | Hypo | 3500, oral | 3 months | ↓ | ↓ | ↑ | At a dose required for equivalent TSH suppression, TA3 has a stronger thyromimetic effect on liver and bones than LT4 | |||||
| Mechelany et al. (1991) | Hypo | 8–17 µg/kg/day TA3 (=500–1000 µg/day) + 1.8 µg/kg/day LT4 (oral) | 6 months | ↓ | ↓ | ↑ | = | ↑ | Compared to LT4 mono-therapy, a 40–50% lower LT4 dose was required once combined with TA3 to obtain equivalent or even better TSH suppression, without affecting TH action in peripheral tissues | |||
| Reduction of lipid levels and body weight in mild obesity | ||||||||||||
| Beck-Peccoz et al. (1988) | Eu | 2800, oral | >2 months | ↓ | No additional effect on body weight and serum cholesterol levels over dietary restrictions alone | |||||||
| Lind et al. (1989)* | Eu | 3000, oral | 8 day | ↓ | = | = | = | No additional effect on body weight and serum cholesterol levels over dietary restrictions alone | ||||
| TSH suppressive therapy in addition to anti-thyroid drugs in Graves’ disease | ||||||||||||
| Pujol et al. (1998) | Eu | ~1350, oral | ~18 months | Effective reduction of goiter size | ||||||||
| TA3 kinetics and general effects | ||||||||||||
| Bracco et al. (1993) | Eu | 1700–3400, oral | 6 week | ↓ | ↓ | ↑ | = | = | Reduction of serum TSH levels with dose-dependent effects on liver and bone, but not BMR | |||
| Eu | 4 dd 350, oral | 3 week | ↓ | More sustained TSH suppression by dividing daily dose | ||||||||
| Burger et al. (1979) | Eu | 150–2400, oral | 1 day | ↓ | Reduction of serum (TRH stimulated) TSH and T3, but not T4 levels, persisting until 5 days after administration | |||||||
| Hyper | 600, oral | 1 day | ↓/= | Reduction of serum T3 levels in 2/7 subjects | ||||||||
| Menegay et al. (1989) | Eu | 350–2800, oral, 1 dose | 1 day | ↓ | Reduction of serum TSH levels after a single dose ≥350 µg | |||||||
| Medeiros-Neto et al. (1980) | Eu, hypo | 1400, oral | 6 week | ↓ | ↓ | = | = | = | Reduction of serum TSH levels, without affecting markers of tissue TH status except cholesterol | |||
| Pregnancy | ||||||||||||
| Cortelazzi et al. (1999) | Eu on PTU | 2100–2800, oral | 13 week | Effective reduction of fetal goiter size, normal neurodevelopment of neonate at 20 months | ||||||||
| Nicolini et al. (1996) | Eu on PTU | 2100–2800, oral | 10 week | Effective reduction of fetal goiter size, normal neurodevelopment the neonate at 20 months | ||||||||
| Asteria et al. (1999) | RTHβ | 2100–3500, oral | 13 week | f | Effective reduction of fetal goiter size. Normal neurodevelopment of neonate (with RTHβ) at 24 months | |||||||
An overview of all studies, of which at least the abstract was available to the authors, in which TA3 has been applied as a treatment for a variety of clinical conditions.
Studies of which only the abstract was available; aWorsening of pre-existent ischemic heart disease (1 case); bWorsening of pre-existent ischemic heart disease (2/12 cases); cWorsening of pre-existent ischemic heart disease (3/18 cases); dNo side effects on cardiac structure in adults; eOnly minor clinical side effects (4/25 participants); fSevere complications due to cordocentesis
BMR, basal metabolic rate; BW, body weight; chol, cholesterol; eu, euthyroid; HR, heart rate; hyper, hyperthyroid; hypo, hypothyroid; myx, myxedema; TO, turn-over.
An overview of the thyromimetic potency of TA3 in different tissues relative to LT4.
| Dose regime | HPT | Liver | Heart | Muscle | Bone | General | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Reference | Thyroid state | TA3 dose | A. LT4Dose B. Δdose LT4 | A. Ratio TA3/LT4dose or B. TA3/ΔLT4ratio | TSH ↓ | TC ↓ | LDL ↓ | HDL ↓ | TG ↓ | SHBG ↑ | Ferritin ↓ | HR ↑ | CK ↓ | Formation ↑ | Resorption ↑ | BMD ↓ | BW ↓ | BMR ↑ |
| A. Comparison to LT4 | ||||||||||||||||||
| Sherman et al. (1997) | hypo | 48 µg/kg/day | 2.2 µg/kg/day | 17 | 17 | <17 | <17 | 17 | 17 | <17 | <17 | 17 | <17 | <17 | ||||
| Bracco et al. (1993) | eu | 23–46 µg/kg/day | 2.4–4.8 µg/kg/day | 9–19 | 9 | 9 | 9 | 9 | >19 | 10 | 19 | 9 | >19 | |||||
| Brenta et al. (2003) | eu | 19.6 µg/kg/day | 1.7 µg/kg/day | 12 | 12 | 12 | 12 | – | 12 | – | – | – | <12 | 12 | ||||
| Ibbertson et al. (1959) | hypo | 5–60 µg/kg/day | 1–3 µg/kg/d | 1.5–20 | 6–10 | 20 | 15 | >15 | ||||||||||
| B. LT4 + TA3 vs LT4 mono-therapy | ||||||||||||||||||
| Mechelany et al. (1991) | hypo | 8.5–17 µg/kg/day | 0.7 µg/kg/day | 13–25 | 13–25 | 13–25 | 13–25 | 13–25 | <13 | >25 | ||||||||
| Sherman & Ladenson (1992) | hypo | 1500 µg | 87 µg | 17 | 17 | <17 | 17 | 17 | <17 | <17 | <17 | (+) | <17 | 17 | 17 | 17 | ||
–, no effect. Only studies in which details of >2 organ systems have been provided are included in this table.
BW, body weight; HR, heart rate; TC, total cholesterol; TG, thyroglobulin.
Basal metabolic rate
Pioneering studies demonstrated that TA3 rapidly increased oxygen consumption in rat kidney slices (Thibault & Pitt-Rivers 1955) and myeloid leukemic leucocytes (Alexander & Bisset 1958) and stimulates aerobic glycolysis in primary tumor cell cultures more potently than T3, T4 or TA4 (Heimberg et al. 1955).
At high doses of 1000–5000 µg/kg/day, TA3 rapidly raised the oxygen consumption in hypothyroid rats (Pitt-Rivers 1953, Wilkinson 1959), whereas a lower TA3 dose of 600 µg/kg/day resulted in a more gradual stimulation (Hill et al. 1960) (Table 2). In hypothyroid patients, TA3 stimulates basal metabolic rate (BMR) only at doses above ~4000 µg/day (50–75 µg/kg/day) (Lerman & Pitt-Rivers 1955, 1956, Trotter 1955, 1956, De Greaff et al. 1957). Trotter (1956) showed that the effects of 4000 µg TA3/day (50–65 µg/kg/day) on BMR persisted beyond 5 days after treatment cessation. In contrast, administration of 45 µg TA3/kg/day for up to 3 weeks to euthyroid subjects significantly reduced BMR and sleeping energy expenditure, presumably due to a reduction of endogenous TH production, whereas protein oxidation was unaffected (Bracco et al. 1993). These parameters significantly increased in subjects treated with 2.4–4.8 µg LT4/kg/day (Bracco et al. 1993). In general, TA3 exerts similar effects on BMR at 4- to 30-fold lower doses of LT4 and 15- to 100-fold lower doses of LT3 (Table 5). Importantly, the TA3 dose required to increase BMR greatly exceeds that required for adequate TSH suppression.
Liver
Intrahepatic TA3 levels increase upon TA3 infusion in rats, which is in line with the important role of the liver in TA3 clearance (Medina-Gomez et al. 2008). TA3 also effectively induces the expression of T3-responsive genes in the liver, including Dio1, to a similar extent as T3 (Juge-Aubry et al. 1995, Liang et al. 1997, Alvarez et al. 2004, Medina-Gomez et al. 2008). No changes in serum cholesterol and lipid levels or biliary excretion were observed after treatment of euthyroid rats for 4 weeks with 200 µg TA3/kg/day (Van Zyl 1957, Autissier et al. 1980).
When given at equivalent TSH-suppressive doses to euthyroid or hypothyroid patients, TA3 induced similar increases in serum sex hormone binding globulin (SHBG) and ferritin levels as LT4 (Bracco et al. 1993, Sherman et al. 1997). In contrast, Beck-Peccoz and coworkers (Beck-Peccoz et al. 1988) and Lind and coworkers (Lind et al. 1989) did not observe any changes in serum SHBG levels upon TA3 administration in a similar dose to mildly obese euthyroid subjects on caloric restriction. In hypothyroid subjects, TA3 also reduced serum total and LDL cholesterol as well as apoprotein B levels, generally within 2 weeks (Table 3). The effect of TA3 on HDL levels was usually less pronounced. These effects of TA3 were generally less pronounced in euthyroid subjects as the effects of TA3 in peripheral tissues were counter-balanced by the reduction in serum T3 induced by TA3, although findings vary depending on the precise TA3 regimen used (Oliver & Boyd 1957, Boyd & Oliver 1960, Medeiros-Neto et al. 1980, Bracco et al. 1993, Brenta et al. 2003). Other liver parameters such as ALAT, ASAT and bilirubin were typically not affected by TA3 (Burger et al. 1979). Taken together, TA3 has potent thyromimetic effects in the liver.
Heart
TA3 is efficiently taken up by rat cardiomyocytes (Medina-Gomez et al. 2008), but is a less potent regulator of TH target genes in the heart than T3 (Liang et al. 1997). Nevertheless, high doses of TA4 induce cardiac hypertrophy in rats, although less potently than T4 (Lameloise et al. 2001). At least part of these effects is likely mediated through TA3. Several rat studies have shown that high doses of TA3 (300 µg/kg/day) administered to pregnant dams induce cardiac hypertrophy and myofibril disorganization in the offspring (Olsen et al. 1977, Hawkey et al. 1981). These abnormalities are less pronounced using a lower TA3 dose (Olsen et al. 1977), or when TA3 is administered to the newborns (Symons et al. 1975), and they are prevented by different β-adrenergic blocking agents with membrane stabilizing properties (Hawkey et al. 1981, Pearce et al. 1983, 1985, 1988). Of note, treatment for 13–19 days with TSH-suppressive doses of TA3 (15–50 µg/kg/day) had no effect on the heart to BW ratio or myocardial structure in adult rats (Olsen et al. 1977, Liang et al. 1997).
In adult human subjects, no detrimental effects of TA3 have been observed on cardiac structure or function (Sherman et al. 1997, Pujol et al. 2000). In general, no overt chronotropic effects have been noted (Tables 2 and 3), although incidentally episodes of palpitations and tachycardia have been reported (Trotter 1956). This may be attributed to its lower potency to activate TRα1 compared with T3 (Koury et al. 2009) or its lack of non-genomic effects on Na+ flux and Ca2+-ATPase activity in cardiomyocytes as observed with T3 (Rudinger et al. 1984, Huang et al. 1999). The effects of TA3 on the heart have not been systematically studied in humans, although several case-reports of children with RTHβ have not reported any cardiac side effects (Anzai et al. 2012).
Adipose tissue
TH importantly regulates basal and facultative thermogenesis, mainly through induction of uncoupling protein Ucp1 in BAT (Nicholis et al. 1986). In rat adipocytes, TA3 appeared more potent in upregulating Ucp1 and Dio2 expression than T3 (Medina-Gomez et al. 2003). Also in vivo, low doses of TA3 resulted in upregulation of Ucp1 in BAT and induced ectopic Ucp1 expression in WAT, without affecting tissue TH levels (Medina-Gomez et al. 2008). In addition, TA3 inhibited leptin expression and secretion in rat brown and white adipocytes (Medina-Gomez et al. 2004).
Bone
TH stimulates bone turnover, particularly bone resorption. Prolonged hyperthyroidism results in a reduction of bone mass and bone mineral density (BMD). Similarly, in vitro studies suggest that the stimulatory effects of TA3 on bone resorption exceed those on bone formation in fetal rat long bones, whereas the overall effects of TA3 on fetal mouse calvarial bones were less pronounced (Kawaguchi et al. 1994a,b).
However, daily injection of 250 µg/kg TA3 in euthyroid rats for 40 days did not increase serum bone alkaline phosphatase (bALP) or carboxy-terminal telopeptide region of type I collagen (β-CTX), which are markers for bone formation and resorption, respectively (Alvarez et al. 2004). In addition, the BMD of the femur did not differ significantly between TA3-treated and control animals (Alvarez et al. 2004). In hypothyroid animals on the same TA3 dose, an increase in β-CTX serum levels was observed without concomitant increase in serum bALP. However, BMD did not differ significantly between TA3-treated and control animals (Alvarez et al. 2004).
In athyroid human subjects, Sherman and coworkers (Sherman et al. 1997) showed that TA3 stimulated bone turnover more potently than LT4, at a similar degree of TSH suppression, as is evidenced by higher ALP and osteocalcin levels (bone formation markers) and urinary pyridinoline and deoxypyridinoline excretion (bone resorption markers). Some studies suggested that TA3 preferentially stimulates bone formation (Mechelany et al. 1991, Sherman & Ladenson 1992), whereas others demonstrate a more selective stimulation of bone resorption and a decrease in BMD of the femoral neck but not of the lumbar spine (Brenta et al. 2003).
Taken together, TA3 stimulates bone resorption and bone formation, although the currently available data are inconclusive regarding the balance between both processes.
Brain and neurogenesis
TA3 regulates the expression of well-known TH target genes, including Dio2 and Dio3, in SH-SY5Y neuroblastoma cells and rat brain homogenates, and stimulates the dendritic arborization of cerebellar Purkinje cells (PCs) as efficiently as T3 (Liang et al. 1997, Horn et al. 2013, Kersseboom et al. 2014).
TA3 also exerts T3-like effects on neurogenesis in vivo. Pax-8 KO mice lack endogenous TH production and consequently have a severely impaired brain development illustrated by a strongly reduced myelination and dendritogenesis of PCs. These abnormalities are largely prevented by administration of 200 µg TA3/kg/day from postnatal day 1 (Kersseboom et al. 2014). The stimulatory effects on myelination are in line with previous studies (Van Wynsberghe et al. 1978). Similar effects have been found with TA4 (Horn et al. 2013). In addition, the administration of low TA3 doses (30 µg TA3/kg/day) to WT mice resulted in a reduction of intracerebral T3 and T4 levels but did not alter the expression levels of some positively regulated TH-dependent genes in the striatum or cerebral cortex (Bárez-López et al. 2016). Several pre-clinical studies in rodents also indicated that TA3 may have an antidepressive effect mediated through its β-adrenergic stimulatory effects (Massol et al. 1987, 1988a,b).
Effects of TA3 and TA4 on the developing human brain are largely unknown. However, several cases have been reported where TA3 has been administered to a pregnant woman for the treatment of fetal hypothyroidism. Cortelazzi and coworkers (Cortelazzi et al. 1999) showed that TA3 administration (2100–2800 µg/day) between 26 and 39 weeks of gestation to a hyperthyroid pregnant woman treated with PTU effectively reduced fetal goiter size within 15 days. A similar case was reported by Nicolini and coworkers (Nicolini et al. 1996). In addition, Asteria and coworkers (Asteria et al. 1999) reported on the use of TA3 in the treatment of a pregnant woman with RTHβ because of suspected hypothyroidism in the fetus carrying the same heterozygous mutation in TRβ. In all three cases, the infant showed a normal neuro(psycho)logical development at 20–24 months of age. Obviously, the risks and benefits of TA3 administration during pregnancy should be carefully weighted. Nevertheless, these studies suggest that TA3 has T3-like effects on the developing human brain.
Skin
Topical application of TA3 increases dermal thickness and prevents glucocorticoid-induced skin atrophy in mice and humans (Faergemann et al. 2002, Yazdanparast et al. 2006a,b), and stimulates procollagen synthesis and keratinocyte proliferation in human skin (Yazdanparast et al. 2004, Zhang et al. 2012), but has no beneficial effects on plaque psoriasis (Vahlquist et al. 2004).
Muscle and kidney
Little is known about the effects of TA3 in muscle and kidney. In hypothyroid rats, TA3 is efficiently taken up in striatal muscle and kidney, where the latter is also an important site for TA3 metabolism (Medina-Gomez et al. 2008). Mechelany and coworkers (Mechelany et al. 1991) have shown that TA3 reduced serum creatine kinase levels. TA3 also increased urinary creatine levels in hypothyroid subjects, suggesting an increase in glomerular filtration rate (Lerman & Pitt-Rivers 1956, Rall et al. 1956, De Graeff et al. 1957, Ibbertson et al. 1959).
Therapeutic applications of TA3 in humans
Because of its thyromimetic properties, the use of TA3 in the treatment of different thyroid diseases has been explored, which is summarized in Table 4.
Myxedema
The therapeutic application of TA3 was first studied in cases of severe hypothyroidism (myxedema). In general, TA3 doses of 10–30 µg/kg/day improved the myxedematous appearance and restored several parameters that reflect tissue TH status, including plasma cholesterol levels, urinary creatine excretion, electrocardiographic abnormalities and body weight, whereas no effect on BMR was observed (Lerman & Pitt-Rivers 1955, 1956, Trotter 1955, 1956, De Graeff et al. 1957, Ibbertson et al. 1959, Boyd & Oliver 1960). Normalization of BMR is generally observed in a dose range of 50–75 µg/kg/day (Table 4). In general, the effects of TA3 occur more rapidly compared to T3 (Zondek et al. 1956, Ibbertson et al. 1959).
Thus, TA3 effectively restores euthyroidism in hypothyroid patients, but is less potent than LT4 and LT3. Taken together, an obvious benefit for the use of TA3 over LT4 in the treatment of myxedematous patients is lacking.
Lipid reduction in coronary heart disease and obesity
The observed dissociated effect of low doses TA3 on serum cholesterol levels and BMR prompted several small studies to the lipid lowering effect of TA3 in euthyroid subjects with coronary heart disease. However, relatively high TA3 doses, up to 5 mg daily (~70 µg/kg/day), were needed to reduce serum cholesterol levels in these studies, with usually only transient effects (Oliver & Boyd 1957, Boyd & Oliver 1960). In non-controlled studies, at doses not affecting BMR, more episodes of transient thoracic pain and increased exercise intolerance have been reported in hypothyroid and euthyroid subjects independent of the TA3 dose, which subsided after TA3 withdrawal (Oliver & Boyd 1957, Ibbertson et al. 1959, Boyd & Oliver 1960). In contrast to these early studies, Brenta and coworkers (Brenta et al. 2003) already observed a reduction in cholesterol levels using a dose of 20 µg TA3/kg/day in healthy subjects.
TA3 has also been studied as a lipid lowering drug in mildly obese euthyroid females with caloric restriction (Beck-Peccoz et al. 1988). Despite a strong reduction in serum TSH, T4 and T3 levels, no significant changes were found in serum cholesterol and triglyceride levels in the TA3 treated group compared with females on caloric restriction alone.
There is no evidence that TA3 is suitable for the long-term control of hypercholesterolemia in euthyroid subjects with or without coronary heart disease.
TSH suppression after thyroidectomy in differentiated thyroid carcinoma
TSH-suppression therapy is initiated after total thyroidectomy in patients with differentiated thyroid carcinoma. Driven by the preferential effects of TA3 on the HPT axis, several studies evaluated TA3 as a TSH-suppressive therapy in such patients.
Mueller-Gartner and Scheider (1988) observed a reduction in mean basal and TRH-stimulated TSH levels in patients on LT4 monotherapy (2.6 ± 0.7 µg/kg/day) upon addition of 500 µg TA3 daily, while only minor side effects were reported in 4 out of 25 patients. However, neither the impact on recurrence and survival rates, nor the effects on the TH state in peripheral organs were evaluated. Pujol and coworkers (Pujol et al. 1997) reported similar findings.
Mechelany and coworkers (Mechelany et al. 1991) compared LT4 monotherapy alone or in combination with TA3. The TA3 dose was adjusted to achieve TSH levels <0.1 U/L, as during LT4 monotherapy. Sherman and Ladenson (1992) performed similar studies, but adjusted the LT4 dose in order to achieve a similar degree of TSH suppression. In both studies, patients required 40–50% less LT4 during combination therapy to achieve equivalent or even better TSH suppression. However, markers that reflect tissue TH action showed only minor or no significant differences between both treatment regimes. These findings implicate that the thyromimetic effects of TA3, at an equal TSH-suppressive dose, are at least as potent as those of LT4 in most peripheral organs.
Sherman and coworkers (Sherman et al. 1997) compared TA3 vs LT4 monotherapy. Following a baseline period (phase I) on a TSH-suppressive dose LT4 (2.7 µg/kg/day), patients received starting doses of 24 µg TA3/kg twice daily or 1.9 µg LT4/kg/day, which were then titrated until TSH levels were below 0.1 U/L (phase II). Subjects receiving TA3 showed a stronger increase in serum levels of SHBG, ferritin, and bone turnover markers, and a stronger decrease in serum total and LDL cholesterol and apoprotein B over baseline levels after 2 months of treatment at the final dose (48 ± 3 µg/kg/day) compared to the LT4 treated group (final dose: 2.2 ± 0.1 µg/kg/day). No significant differences were observed in cardiac parameters, energy expenditure or body weight between both groups. Remarkably, upon dose-escalation subjects in the LT4 treated group received a 10–20% lower final LT4 dose in phase II than during phase I of the study. Moreover, it appears that it was not required to further escalate the TA3 starting dose of 24 µg TA3/kg twice daily in order to obtain TSH suppression <0.1 U/L.
In conclusion, TA3 monotherapy is an adequate TSH-suppressive therapy, while at the same time providing sufficient thyromimetic effects in the peripheral tissues. TA3 may especially have augmented thyromimetic effects on the pituitary, liver and bone. Based on the available studies, there is no obvious benefit of using TA3, alone or in combination with LT4, as TSH-suppression therapy, unless LT4 is not tolerated.
Goiter
Brenta and coworkers (Brenta et al. 2003) showed that TA3 (19.6 µg/kg/day) and LT4 (1.7 µg/kg/day) were equally effective in reducing goiter size in patients with euthyroid goiter, although the proportion of patients in whom goiter size was reduced by more than 50% was higher in the TA3 (42%) vs LT4 (17%) treated group (although not statistically significant), while less side effects were reported. TSH levels were adequately reduced in both groups and FT4 levels decreased in the TA3 treated group. Most parameters that reflect peripheral TH state, including heart rate, showed insignificant changes in both treatment arms. Nevertheless, a significant decrease in serum total and LDL cholesterol as well as femoral BMD and increased deoxypyridinoline levels were observed in the TA3 treated patients, which suggest an increase in bone resorption.
Pujol and coworkers (Pujol et al. 1998) studied the effect of TA3 and T3 as a TSH-suppressive therapy in addition to the anti-thyroid drug carbimazole in the treatment of Graves’ disease, which both significantly reduced goiter volume, but did not significantly improve remission and relapse rates of Graves’ disease.
Taken together, TA3 treatment effectively reduces goiter volume in patients with (non-)toxic diffuse and nodular goiter. Since TSH-suppressive therapy is not recommended as useful goiter-reductive treatment, neither LT4 nor TA3 is advised for goiter reduction.
TA3 abuse in dietary supplements
Multiple cases have been reported over the last decades on the abuse of dietary supplements, metabolic enhancers and mesotherapies containing TA3. Subjects presented with clinical signs of thyrotoxicosis, while TH and TSH levels were found to be suppressed (Ferner et al. 1986, Chow & Lam 1998, Bauer et al. 2002, Scally & Hodge 2003, Chan et al. 2004, Ma et al. 2008, Danilovic et al. 2008, Cohen-Lehman et al. 2011). For this reason, the US Food and Drug Administration has repeatedly issued an official warning against the consumption of dietary supplements or metabolic enhancers containing TA3.
Application of TA3 in RTH syndromes
RTH syndromes results from alteration of local TH signaling due to defective cellular entry, intracellular metabolism or receptor function. The finding that TA3 clearly exerts thyromimetic effects but differs from T3 in its cellular transport mechanism and affinity for mutant TRβ variants, prompted studies to explore the application of TA3 (and TA4) in RTHβ and MCT8 deficiency.
RTHβ
RTHβ is caused by mutations in TRβ and biochemically characterized by elevated serum TH levels in the context of non-suppressed TSH levels. RTHβ results in decreased T3 action in tissues that express TRβ, whereas tissues that predominantly express TRα, such as the heart and brain, are relatively thyrotoxic in response to the high serum TH levels (Refetoff et al. 1993, Forrest et al. 1996). In vitro studies have shown that TA3 is able to bind and activate a subset of these mutant receptors (Takeda et al. 1995). The effects of TA3 treatment in RTHβ patients have been described on a case-by-case basis and are currently the most wide-spread off-label application of TA3. In a subgroup of RTHβ patients, TA3 is able to decrease TSH and consequently the high serum T4 and T3 levels. Since the thyromimetic effects of TA3 itself do not fully compensate the reduction in endogenous TH levels, it alleviates the thyrotoxic symptoms including tachycardia, goiter, excessive sweating and behavioral problems (Beck-Peccoz et al. 1983, Lind & Eber 1986, Faglia et al. 1987, Salmela et al. 1988, Kunitake et al. 1989, Smallridge et al. 1989, Beck-Peccoz et al. 1990, Aguilar Diosdado et al. 1991, Crino et al. 1992, Dulgeroff et al. 1992, Ueda et al. 1996, Darendeliler & Basx 1997, Radetti et al. 1997, Clifton-Bligh et al. 1998, Persani et al. 1998, Asteria et al. 1999, Kong et al. 2005, Torre et al. 2005, Wu et al. 2006, Gurgel et al. 2008, Santos et al. 2008, Guran et al. 2009, Anzai et al. 2012, Ferrara et al. 2012, Ramos-Prol et al. 2013, Stagi et al. 2014, Chatzitomaris et al. 2015, Xue et al. 2015). However, some patients do not respond to TA3 treatment, which is assumed to depend on the type or location of the mutation (Hamon et al. 1988, Persani et al. 1998). These reports have been reviewed in more detail in Groeneweg and coworkers (Groeneweg et al. 2017). In order to prevent overtreatment, pre-clinical analysis of the impact of mutations on T3 and TA3 binding and transactivation potency may predict which patients benefit from TA3 treatment.
MCT8 deficiency
Mutations in MCT8 result in the AHDS, which is characterized by severe intellectual and motor disability and increased serum T3 levels (Dumitrescu et al. 2004, Friesema et al. 2004). Transport of TH across the BBB and into neuronal cells largely depends on MCT8. Hence mutations in MCT8 result in a hypothyroid state in the brain, compromising brain development (Matheus et al. 2015). In contrast, tissues that rely on other transporters are exposed to the high serum T3 levels resulting in thyrotoxic tissues. Putative therapies should aim to restore TH signaling in the brain and at the same time alleviate the thyrotoxic state in the peripheral tissues. Although combination therapy of LT4 and PTU alleviates the peripheral thyrotoxicosis, this approach does not restore TH signaling in the brain (Visser et al. 2013). The ideal therapy comprises a TH analog that enters the cell independently from MCT8, but exerts similar effects as TH. As outlined in this review, TA3 fulfills these criteria (illustrated in Fig. 2). Indeed, several pre-clinical studies have supported the therapeutic potency of TA3 and its less rapidly metabolized precursor TA4 in AHDS.
Schematic representation of a T3 target cell that relies on MCT8 for its TH uptake. The proposed working mechanism of TA3 (and other TH analogues) in case of defective MCT8 entails cellular uptake in an MCT8-independent way, binding to the TRs and preferably degradation through similar pathways as TH, which are all fulfilled by TA3 as outlined in this review.
Citation: Journal of Endocrinology 234, 2; 10.1530/JOE-17-0113
Mct8 KO mice show the characteristic serum TFT pattern of AHDS (Trajkovic et al. 2007, Trajkovic-Arsic et al. 2010), which is effectively normalized by TA4 treatment (Horn et al. 2013). However, Mct8 KO mice lack a neurological phenotype, since Oatp1c1 is likely to function as an alternative TH transporter at the BBB in mice. Indeed, in Mct8/Oatp1c1 double KO (DKO) mouse brain development is severely disturbed and closely resembles the abnormalities observed in Pax-8 KO mice (Mayerl et al. 2014). The abnormal brain morphology in Pax-8 KO mice is largely prevented by administration of T3, TA3 (200–400 µg/kg/day) or TA4 (400 µg/kg/day) from postnatal day 1 (Horn et al. 2013, Kersseboom et al. 2014), suggesting that TA3 and TA4 can replace T3 and T4 during brain development in mice. Such effects of TA4 were also observed in Pax-8/Mct8 DKO mice, confirming that its transport across the BBB is MCT8-independent. Most importantly, TA3 administration (400 µg/kg/day) from postnatal day 1–12 rescued several markers of disrupted brain development in Mct8/Oatp1c1 DKO mice, including the abnormal cerebellar Purkinje cell development and myelination (Kersseboom et al. 2014). In addition, TA3 and TA4 ameliorate the neurodevelopmental abnormalities in zebrafish models for MCT8-deficiency (De Vrieze et al. 2014, Zada et al. 2016) and improve cerebellar Purkinje cell development in Mct8 deficient chicken (Delbaere et al. 2017). So far, it has not been studied in these animal models to what extent TA3 still has positive effects on brain development once treatment is initiated at a later developmental stage. This is particularly important to predict its therapeutic potency in human AHDS patients, when initiated at a relatively advanced age.
The putative role of TA3 as a therapy for human AHDS patients is currently under investigation in a prospective interventional cohort study, the Triac Trial (Nbib2060474), primarily assessing its potency to restore the peripheral thyrotoxicosis. If TA3 would be an effective therapy, it can be anticipated that early intervention may have effects on the neurocognitive phenotype. Although TA3 readily crosses the placenta (Asteria et al. 1999, Cortelazzi et al. 1999), there are many medical and ethical considerations before justifying prenatal administration of TA3 to mothers who are pregnant of an AHDS child.
Concluding remarks
TA3 is a bioactive TH metabolite that has tissue-specific thyromimetic activities (Table 5). Although TA3 clearly has a potent TSH-suppressive effect, its metabolic effects on liver and bone are at least as potent. In general, higher doses of TA3 are required to achieve equal thyromimetic effects as LT4 (and LT3), mainly due to its rapid clearance. Based on the available studies, the therapeutic benefits of TA3 over LT4 treatment is generally limited to primary thyroid diseases. However, TA3 holds potential in the treatment of subsets of RTHβ patients and possibly in AHDS. Clinical studies are needed to assess if and how this ‘old’ molecule can have full therapeutic potential in specific RTH syndromes.
Declaration of interest
W E V is the principal investigator of the Triac Trial in MCT8 patients (Nbib2060474).
Funding
This work was supported by a grant from the Netherlands Organisation for Health Research and Development (project number 113303005, 2014) (to W E V) and from the Sherman Foundation (to W E V, 2016).
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